Mechanism of Amine-Catalyzed Ester Formation from an Acid Chloride and Alcohol

Article abstract of DOI:10.1021/jo9716643

Stopped-flow FT-IR spectroscopy has been used to study the amine-catalyzed reactions of benzoyl chloride with either butanol or phenol in dichloromethane at 0 °C. There is a paucity of detailed rate information available in the literature for this process. Our goal was to determine whether amine catalysis operated by a nucleophilic-, specific-base-, or general-base-catalyzed mechanism. A large isotope effect was observed for butanol versus butanol-O-d which is consistent with a general- base-catalyzed mechanism. Some anomalous rate dependencies on reactant concentration and the relative rate of benzoyl chloride loss versus butyl benzoate formation were observed. The analogous reaction of phenol was studied in more detailed. An overall reaction order of three, and a negligible isotope effect for phenol versus phenol-d₆ are consistent with either a base- or nucleophilic-catalyzed mechanism. The most interesting result with phenol was a large sensitivity of the rate of phenyl benzoate formation on small structural changes in the amine (e.g., diethylmethylamine versus triethylamine). We observed the key intermediate (acylammonium salt) in the nucleophilic process via NMR for solutions of benzoyl chloride and amine in the absence of alcohol; however, we did not observe this intermediate in the IR during ester formation [with the exception of 4-(dimethylamino)- pyridine]. While we can rule out specific-base catalysis (no evidence for phenoxide intermediates), it is difficult to completely eliminate nucleophilic catalysis.

Full text of DOI:10.1021/jo9716643

J . Org. Chem. 1998, 63, 677-683
677
Mech a n ism of Am in e-Ca ta lyzed Ester F or m a tion fr om a n Acid
Ch lor id e a n d Alcoh ol
Patricia Hubbard and William J . Brittain*
Department of Polymer Science, The University of Akron, Akron, Ohio 44325-3909
Received September 8, 1997
Stopped-flow FT-IR spectroscopy has been used to study the amine-catalyzed reactions of benzoyl
chloride with either butanol or phenol in dichloromethane at 0 °C. There is a paucity of detailed
rate information available in the literature for this process. Our goal was to determine whether
amine catalysis operated by a nucleophilic-, specific-base-, or general-base-catalyzed mechanism.
A large isotope effect was observed for butanol versus butanol-O-d which is consistent with a general-
base-catalyzed mechanism. Some anomalous rate dependencies on reactant concentration and the
relative rate of benzoyl chloride loss versus butyl benzoate formation were observed. The analogous
reaction of phenol was studied in more detailed. An overall reaction order of three, and a negligible
isotope effect for phenol versus phenol-d6 are consistent with either a base- or nucleophilic-catalyzed
mechanism. The most interesting result with phenol was a large sensitivity of the rate of phenyl
benzoate formation on small structural changes in the amine (e.g., diethylmethylamine versus
triethylamine). We observed the key intermediate (acylammonium salt) in the nucleophilic process
via NMR for solutions of benzoyl chloride and amine in the absence of alcohol; however, we did not
observe this intermediate in the IR during ester formation [with the exception of 4-(dimethylamino)-
pyridine]. While we can rule out specific-base catalysis (no evidence for phenoxide intermediates),
it is difficult to completely eliminate nucleophilic catalysis.
Sch em e 1
In tr od u ction
Cyclic oligomers of engineering thermoplastics are
promising precursor materials for reactive processing
because of their low melt viscosity and their ability to
undergo facile ring-opening polymerization. Brunelle
and co-workers have developed high-yield processes for
the synthesis of macrocyclic oligocarbonates.1 Brunelle’s
methodology uses a Ziegler-Ruggli dilution method
(sometimes called pseudo-high-dilution) that allows high
product concentrations. In addition, the synthetic ap-
proach minimizes linear oligomers and produces a dis-
tribution of cyclic oligomers (as opposed to a preponder-
ance of a single oligomer) which is advantageous for lower
melt polymerization temperatures.
Recently, Brunelle and co-workers have published
results on alkylene phthalate cyclic oligomers. Two
methods have been described for the preparation of these
macrocyclic oligoesters. One is the ring-chain equilibra-
tion from linear polymers.2 Bryant and Semlyen3 have
also described the preparation and characterization of
cyclic oligomers of poly(ethylene terephthalate) (PET)
using the ring-chain process.
obtained with sterically unhindered amines such as
quinuclidine. Triethylamine, pyridine, and 4-(dimethyl-
amino)pyridine led to small amounts (<5%) of cyclic
oligomers. Higher yields of cyclics were obtained with
quinuclidine and l,4-diazabicyclo[2.2.2]octane (DABCO).
Optimization of cyclization conditions eventually led to
a process which uses catalytic amounts of DABCO in
conjunction with stoichiometric quantities of triethyl-
amine; this process produces up to 85% yields of poly-
(butylene terephthalate) (PBT) cyclic oligomers.
Our interest in the utility of these macrocyclization
reactions prompted us to investigate the mechanism of
ester formation. It was felt that rational control of yields
and ring-size distribution would be best achieved through
an understanding of the mechanism of amine catalysis.
The fundamental reaction involved in the oligoester
macrocyclization is the amine-catalyzed formation of an
ester from an acid chloride and an alcohol. The balance
of intramolecular vs intermolecular ester bond formation
controls the amount of cyclization versus chain extension.
We have found scant kinetic information in the litera-
ture on amine-catalyzed reactions of acid chlorides in
aprotic, nonpolar solvents. It is generally recognized that
these reactions are extremely rapid and, thus, difficult
A second method (Scheme 1) is based on the amine-
catalyzed reaction of acid chlorides with diols.4,5 The
yield of the cyclic oligomers is strongly dependent on the
structure of the amine catalyst, with the highest yields
(1) Brunelle, D. J . In Macromolecular Design of Polymeric Materials;
Hatada, K., Kitayama, T., Vogl, O., Eds.; Marcel Decker: New York,
Chapter 16, 1997.
(2) Brunelle, D. J .; Takekoshi, T. U. S. Patent 5 407 984, 1995.
(3) Bryant, J . J . L.; Semlyen, J . A. Polymer 1997, 38, 2475.
(4) (a) Brunelle, D. J .; Bradt, J . E. U.S. Patent 5 039 783, 1991. (b)
Brunelle, D. J .; Bradt, J . E.; Serth-Guzzo, J .; Takekoshi, T.; Evans, T.
L.; Pearce, E. J . Polym. Prepr. 1997, 38, 0000.
(5) Hubbard, P. A.; Brittain, W. J .; Simonsick, W. J ., J r.; Ross, C.
W., III Macromolecules 1996, 29, 8304.
(6) Kivinen, A. In The Chemistry of Acid Halides; Patai, S., Ed.;
Interscience: New York, Chapter 6, 1972.
S0022-3263(97)01664-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

678 J . Org. Chem., Vol. 63, No. 3, 1998
Hubbard and Brittain
to study.6 There have been some reports on the alco-
holysis of acid chlorides in aprotic solvents without amine
catalysis.7,8 However, most literature work on the amine-
catalyzed reactions of carbonyl compounds has been
performed in protic solvents. A number of putative
mechanisms have been proposed on the basis of these
reports. Examples of general-base catalysis include the
acetate-catalyzed hydrolysis of acetic anhydride9 and
several imidazole-catalyzed reactions of acetates.10,11 In
the hydrolysis of acetic anhydride, acetate ion acts as a
base in the proton abstraction from a water molecule
which is attacking the ester. The majority of the litera-
ture on amine-catalyzed reactions proposes a nucleophilic
catalysis mechanism where the amine attacks the car-
bonyl bond, forming a transient tetrahedral intermediate;
on displacement of the leaving group, a quaternary
acylammonium salt (AAS) is formed. The AAS is then
susceptible to attack by water, alcohol, or other nucleo-
phile to form product. One fundamental study in this
area was done by Fersht and J encks.12 They studied the
pyridine-catalyzed hydrolysis of acetic anhydride; a nu-
cleophilic mechanism was supported by several pieces of
experimental evidence, including a slower rate of hy-
drolysis for 2-substituted pyridines. However, no direct
observation of the acylammonium salt was reported.
Other proposed mechanisms for amine-catalyzed reac-
tions of carbonyl compounds have involved acylium ion9
and ketene intermediates (the latter can only occur for
acid halides containing R-hydrogens).10
The mechanism of amine-catalyzed reactions of car-
bonyl compounds is determined by the reacting species
as well as the reaction conditions. J ohnson13 reviewed
the factors which determine whether a reaction follows
a nucleophilic versus a base-catalyzed pathway. Nucleo-
philic catalysis mechanisms are indicated to be favored
by good leaving groups, electronegative acyl groups,
unhindered bases, and strongly basic nucleophiles.
Perhaps for the present study, previous work in our
laboratories on the amine-catalyzed reaction of bisphenol
A (4,4′-isopropylidenediphenol) bischloroformates is more
relevant.14 Similar to ester macrocyclization, the yield
of cyclic carbonate oligomers is strongly dependent on the
amine structure. In the cyclic carbonate case, the forma-
tion of AAS is directly observable via IR. The rate of AAS
formation was found to be strongly dependent on amine
structure. This dependence is in contrast to other
reactions in the macrocyclization process (e.g., carbonate
and carbamate formation) which were insensitive to the
amine structure. This earlier work provides strong
evidence in support of an active nucleophilic catalysis
mechanism for amine-catalyzed macrocyclization reac-
tions.
F igu r e 1. Representative data for the loss of benzoyl chloride,
BC (b), and formation of phenyl benzoate, PB ( ), as a function
*
of time using triethylamine (dichloromethane, 0 °C); [BC]0 )
[phenol]0 ) [Et3N]0 ) 0.0167 M.
butanol in dichloromethane. We have used stopped-flow
techniques to facilitate the observation of these fast
reactions.
Resu lts
The model reaction between benzoyl chloride and an
alcohol to form a benzoate ester can be monitored by
stopped-flow FT-IR spectroscopy. This technique was
used previously to study the mechanism of carbonate
macrocyclization.15 Both the acid chloride and ester could
be quantitatively monitored via their carbonyl absorp-
tions in the IR spectrum. Benzoyl chloride displays two
carbonyl bands, at 1775 and 1734 cm-1; the splitting is
a consequence of a Fermi interaction.16 The carbonyl
absorption of phenyl benzoate (1734 cm-1) is coincident
with one band of benzoyl chloride while butyl benzoate
displays a carbonyl absorption at 1712 cm-1
. Molar
absorptivities were determined and used to calculate
concentrations from the spectra. The formation of phenyl
benzoate was monitored by changes in the 1734 cm-1
peak after correction for the amount of benzoyl chloride
(estimated from the area of the peak at 1775 cm-1). Ester
formation was relatively fast (several seconds to 1 h) with
few side reactions. If anhydrous conditions were not
maintained, anhydride formation was observed due to the
rapid hydrolysis of the acid chloride to the carboxylic acid.
In determining the rate of reaction, both the decrease
of benzoyl chloride (-d[BC]/dt) and the increase in either
phenyl benzoate or butyl benzoate (d[PB]/dt, d[BB]/dt)
with time were measured. The decrease in benzoyl
chloride concentration was determined using the eq 1.
[BC]0 - [BC]t
d[BC]
dt
-
)
(1)
To shed further light on the mechanism of amine-
catalyzed ester bond formation from the reaction of an
acid chloride with an alcohol, we have studied the model
reactions of benzoyl chloride with either phenol and
t
The rates of formation of the phenyl benzoate and butyl
benzoate were similarly calculated. In experiments
where no intermediate was observed in the IR, the rates
of starting material loss and product formation are
expected to be similar. The rate of the reaction was
calculated from the initial slope of the concentration
(7) Kevill, D. N.; Foss, F. D. J . Am. Chem. Soc. 1969, 91, 5054.
(8) Bayliss, M. A. J .; Homer, R. B.; Shepard, M. J . J . Chem. Soc.,
Chem. Commun. 1990, 305.
(9) Kilpatrick, M. J . Am. Chem. Soc. 1928, 50, 2981.
(10) J encks, W. P.; Cariuolo, J . J . Am. Chem. Soc. 1961, 83, 1743.
(11) Kirsch, J . F.; J encks, W. P. J . J . Am. Chem. Soc. 1964, 86, 837.
(12) Fersht, A. R.; J encks, W. P. J . J . Am. Chem. Soc. 1970, 92, 5432.
(13) J ohnson, S. L. In Advances in Physical Organic Chemistry; Gold,
V., Ed.; Academic Press: London, 1967; Vol. 5, pp 271-317.
(14) Aquino, E. C.; Brittain, W. J .; Brunelle, D. J . Macromolecules
1992, 25, 3827.
(15) Brittain, W. J .; Aquino, E. C.; Dicker, I. B.; Brunelle, D. J .
Makromol. Chem. 1993, 194, 1249.
(16) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds; J ohn Wiley & Sons: New York,
1991; p 120.

Amine-Catalyzed Ester Formation
J . Org. Chem., Vol. 63, No. 3, 1998 679
Sch em e 2
Sch em e 3
F igu r e 2. Isotope effect for the reaction of benzoyl chloride
(BC) with phenol versus phenol-d6 in the presence of triethyl-
amine in dichloromethane at 0 °C; [BC]0 ) [phenol]0 ) [Et3N]0
) 0.067 M.
versus time data. In this region, the slope was nearly
linear. A typical concentration-time plot is shown in
Figure 1.
Kin etic Mod el. We discounted ketene formation
(because benzoyl chloride has no R-hydrogens) and acy-
lium ions (because dichloromethane is a relatively non-
polar medium) as viable reactions.17 Our mechanistic
study focused on distinguishing between nucleophilic
versus base catalysis. Scheme 2 depicts the nucleophilic
mechanism for benzoate ester formation where the first
step produces an AAS. The AAS reacts with an alcohol
in the second step to form ester. Both steps 1 and 2 are
assumed to proceed via a tetrahedral intermediate in
accordance with the normal addition-elimination se-
quence of carbonyl addition reactions. Therefore, Scheme
2 depicts a simplified mechanism. If the first step is rate
determining, then k-1 is much smaller than k2[R′OH] and
is assumed to be negligible, leading to eq 2.
F igu r e 3. Isotope effect for the reaction of benzoyl chloride
(BC) with phenol versus phenol-d6 in the presence of DABCO
in dichloromethane at 0 °C; [BC]0 ) [phenol]0 ) [DABCO]0 )
0.0167 M.
base to give a partial negative charge on oxygen; this
alcohol-amine complex would then react with benzoyl
chloride to form product. General-base catalysis would
be a third-order reaction. Isotope effects have been useful
in the diagnosis of general-base catalysis.18 A comparison
of isotope effects in substitution reactions at carbonyl
carbons shows values greater than 2 for general-base
catalysis and values near 1 (no isotope effect) for reac-
tions following nucleophilic catalysis. An isotope effect
would also be possible if the first step in specific-base
catalysis is rate determining.
P h en yl Ben zoa te F or m a tion . Isotop e Effect. Ex-
periments were run to determine if a primary isotope
effect exists in the reaction of phenol with benzoyl
chloride when catalyzed by either triethylamine or
DABCO. A decrease in reaction rate with phenol-d6
relative to phenol would indicate O-H (O-D) bond
cleavage in the rate-determining step, as predicted for
base catalysis. Results are shown in Figures 2 and 3. In
both cases, reaction rates for phenol and phenol-d6 were
nearly identical, indicating a small or negligible isotope
effect. The apparent lack of an isotope effect does not
rule out any of the mechanisms.
d[BC]
dt
-
) k1[BC][NR3]
(2)
If the second step is rate determining, the rate expres-
sion is third-order overall, being first order in each of the
reactants as shown in eq 3.
k1k
d[BC]
-
)
2[BC][NR3][R′OH]
(3)
dt
k-1
A simplified mechanism for specific-base catalysis is
shown in Scheme 3. Specific-base catalysis requires that
the amine remove a proton from the alcohol to form an
alkoxide which can then attack benzoyl chloride. If the
acid-base reaction in step 1 is rate-determining, the rate
expression is second-order, eq 4.
d[BC]
dt
-
) k3[R′OH][NR3]
(4)
If the second step is rate-determining, the reaction is
third-order overall as shown in eq 5.
k3k
d[BC]
Ra te Or d er . The rate order of each species in the
triethylamine-catalyzed reaction of benzoyl chloride with
-
)
4[BC][NR3][R′OH]
k-3
(5)
dt
(17) Bentley, T. W.; Carter, G. E.; Harris, H. C. J . Chem. Soc., Perkin
Trans. 2 1985, 983.
(18) J ohnson, S. L. In Advances in Physical Organic Chemistry; Gold,
V., Ed.; Academic Press: London, 1967; Vol. 5, p 281.
General-base catalysis is similar to specific-base ca-
talysis except the discrete formation of phenoxide ion is
not required. Instead, the alcohol coordinates with the

680 J . Org. Chem., Vol. 63, No. 3, 1998
Hubbard and Brittain
F igu r e 4. Rate-order plot for benzoyl chloride (BC) reaction
with phenol in the presence of triethylamine (dichloromethane,
0 °C).
F igu r e 5. Rate-order plot for benzoyl chloride (BC) reaction
with phenol in the presence of DABCO (dichloromethane, 0
°C).
Ta ble 1. Ra te Or d er s for P h en yl Ben zoa te F or m a tion a ,b
section describes experiments aimed at detection of these
putative intermediates. UV-vis spectroscopy can be
used to distinguish between phenol and phenoxide.
Tetraethylammonium phenoxide displayed an absorption
maximum at 250 nm in dichloromethane and under the
same conditions, phenol displayed a small peak at 228
nm and a stronger absorption at 275 nm. However, when
a solution of phenol and triethylamine was prepared in
dichloromethane and the UV-vis spectrum recorded, no
evidence of phenoxide was observed. Therefore, under
the experimental conditions used for ester formation, we
did not observe a discrete phenoxide ion (detection level
of phenoxide ≈5%). This result argues against a specific-
base-catalyzed mechanism.
In previous work, we observed AAS formation during
the reaction of phenylchloroformate with tertiary amines.14
The AAS is characterized by its unique carbonyl absorp-
tion in the IR. In the present study, reaction of benzoyl
chloride with different amines at 0 °C in the absence of
phenol gave mixed results. Only 4-(dimethylamino)-
pyridine (DMAP) led to AAS formation, as evidenced by
a new absorption at 1739 cm-1. Triethylamine, quinu-
clidine, and DABCO did not form AAS in the IR experi-
ments. The undetectable level of AAS may be the result
of the electrostrictive effect20 in which a large charge
dipole destabilizes species such as the AAS in aprotic,
nonpolar solvents.
Because of the -10 °C lower temperature limit in the
IR experiments, we chose to extend the temperature
range for observations by using NMR to further inves-
tigate AAS formation.21,22 Equimolar amounts of amine
and benzoyl chloride in dichloromethane-d2 were studied
over the temperature range of -60 to -90 °C. The
amines studied included triethylamine, DABCO, and
DMAP. DMAP reacted completely to form AAS with the
aromatic nitrogen of DMAP attacking the benzoyl chlo-
ride. The NMR shifts were consistent with the results
of King and Bryant22 for the AAS of benzoyl chloride and
DMAP that was prepared using nonnucleophilic counte-
rions. DABCO was partially converted to AAS over the
temperature range studied; the most diagnostic reso-
nance was that for the ortho hydrogens of benzoyl
chloride which shifted from a doublet at 8.21 ppm to a
broad peak at 8.31 ppm at -90 °C. On the basis of the
component
Et3N
benzoyl chloride
phenol
-d[BC]/dt
-d[PB]/dt
1.0
1.0
1.3
0.8
1.0
1.2
a
Triethylamine-catalyzed reaction of benzoyl chloride and
phenol; -d[BC]/dt ) rate of benzoyl chloride loss, [PB]/dt ) rate
b
of phenyl benzoate formation. Experimental error in rate order
values is (0.1.
phenol was measured to help distinguish between specific-
base catalysis and nucleophilic catalysis. For rate order
data to distinguish between these two mechanisms, the
first step of either reaction would need to be rate-
determining. Otherwise, the reaction will be third-order
overall for both mechanisms.
To determine reaction orders, reactions were run under
pseudo-first-order conditions (see Experimental Section)
where the starting concentration of the component of
interest was 5-fold lower relative to other reactants. The
log plot of the initial rate against the log of the initial
concentration gives a line whose slope equals the reaction
order.19 Figure 4 shows the rate-order plot for benzoyl
chloride.
The results for three reactants are summarized in
Table 1. The reaction was found to be third-order overall
and first-order in each reactant. This result is consistent
with either base catalysis or nucleophilic catalysis.
Therefore, under our conditions, the mechanisms are
indistinguishable on the basis of rate-order analysis.
Triethylamine was chosen as the catalyst in this study
because its reaction times were slow enough that small
variations in reaction rates could be monitored ac-
curately. Concerned that the rate-order results might
vary for different amine catalysts, we also studied the
rate order of DABCO. Figure 5 shows the rate-order plot
for DABCO. We observed a second-order dependence (2.0
when determined by benzoyl chloride loss and 1.7 when
determined by phenyl benzoate formation). A second-
order dependence for DABCO may indicate a dual role
for DABCO, where it simultaneously operates by both
mechanisms.
Rea ction In ter m ed ia tes. Each of the proposed
mechanisms is associated with a key intermediate; the
AAS in the nucleophilic process and an ammonium
phenoxide in the specific-base-catalyzed process. This
(20) King, J . A., J r. J . Am. Chem. Soc. 1988, 110, 5764.
(21) Brunelle, D. J .; Boden, E. P. Makromol. Chem., Macromol.
Symp. 1992, 54/55, 397.
(19) Schmid, R.; Sapunov, V. N. Non-Formal Kinetics; Verlag
Chemie: Weinheim, 1982.
(22) King, J . A., J r.; Bryant, G. L. J . Org. Chem. 1992, 57, 5136.

Amine-Catalyzed Ester Formation
J . Org. Chem., Vol. 63, No. 3, 1998 681
Ta ble 2. Acyl Am m on iu m Sa lt F or m a tion fr om Ben zoyl
Ch lor id ea
clidine was fast enough that the early part of the reaction
could not be monitored, so the ester formation rate is
greater than 0.1 M/s.
% acyl ammonium salt
It is recognized that using aqueous pKa values for
reactions in aprotic, nonpolar media can be misleading.
However, we perform this exercise to search for trends
that might shed light on the mechanism. Comparing
rates with pKa values does not reveal a strong correlation
with amine basicity. Quinuclidine and triethylamine
were the two most basic amines, and the their rates
differed by at least 3 orders of magnitude. These facts
are inconsistent with a base-catalyzed mechanism which
should show a rate increase with increased basicity. This
conclusion assumes that the relative amine basicity
values measured in water are a reasonable measure of
basicity trends in dichloromethane.
temp (°C)
DMAP
DABCO
Et3N
0b
-60c
-90c
100
100
100
0
62
76
0
0
24
Experimental error ) 3%. IR result. c NMR result.
a
b
Ta ble 3. P h en yl Ben zoa te F or m a tion : Ra te vs Am in ea
amineb
DMAP
quinuclidine
DABCO
Et2MeN
N-MeP
Et3N
Pr3N
pyridine
pKa
-d[BC]/dt,c M/s
d[PB]/dt,c M/s
9.45d
10.95e
8.77f
>0.3
>0.1
>0.3
>0.05
0.00373
0.00215
0.00128
0.00028
0.00011
2.1 × 10-6
0.00277
0.00223
0.00135
0.00025
0.0001
10.43g
10.19g
10.75e
10.66g
5.21e
There is a correlation between rates and AAS stability
as predicted by SYBYL. Except for diethylmethylamine,
the rates followed the same ranking as the AAS stabili-
ties. This correlation supports a nucleophilic mechanism
which requires AAS formation in the first step.
1.7 × 10-6
a
[BC]0 ) [phenol]0 ) [amine]0 ) 0.0167 M, dichloromethane, 0
°C; all rate values are the average of at least two separate runs;
b
experimental error never exceeded 5% of reported value. N-MeP
Su m m a r y of P h en yl Ben zoa te Stu d y. The results
of our investigation into the reaction between benzoyl
chloride and phenol may be consistent with a nucleophilic
mechanism for amine catalysis. The lack of phenoxide
in the UV-vis work rules out specific-base catalysis. The
AAS intermediate in the nucleophilic mechanism was
observed in low-temperature NMR experiments. The
rate of ester formation as a function of amine structure
showed a correlation between AAS stability (as deduced
from molecular modeling) and rate. Of course, the NMR
observation of AAS may be unrelated to the reaction
pathway for ester formation. Also, we recognize that the
molecular modeling was performed at an unsophisticated
level. What cannot be disputed is the rate data we report
which shows a subtle sensitivity to modest changes in
amine structure.
The ramification of a nucleophilic-catalysis mechanism
for ester macrocyclization is obvious. There is a strong
correlation between reaction rate and yield of cyclics
formed, with faster reactions leading to higher yields of
cyclics (DMAP was the only exception). As might be
expected, faster reactions would minimize the concentra-
tion of end groups and thus favor cyclization. Slow ester-
forming reactions would lead to a build-up of reactants
during the addition process used in the cyclization
methodology; the occurrence of intermolecular reactions
would increase relative to the intramolecular reactions,
and thus decrease the yields of cyclics.
Bu tyl Ben zoa te F or m a tion . A better model reaction
for PET and PBT cyclic ester formation is the reaction
between benzoyl chloride and butanol. This reaction was
not studied initially due to technical difficulties which
produced side reactions (hydrolysis). The mechanistic
study of butyl benzoate formation produced substantially
different results. We view butyl benzoate formation to
be analogous to phenyl benzoate formation in terms of
proposed mechanisms (nucleophilic versus base cata-
lyzed) and mechanistic strategy. The primary difference
between these two reactions is the reactivity of butanol
versus phenol; phenol is more acidic than butanol.
Effect of Am in e Str u ctu r e on Ra te of Bu tyl Ben -
zoa te F or m a tion . Four amines were studied to see if
the rate trends for butanol were the same as for phenol.
Table 4 shows that the four amines studied fall in the
same order with respect to their effect on benzoyl chloride
) N-methylpiperidine. c -d[BC]/dt ) rate of benzoyl chloride loss,
d
d[PB]/dt ) rate of phenyl benzoate formation. Reference 23.
e Reference 24. f Reference 25. Reference 26.
g
integrated areas of these two peaks, we observed 62%
AAS at -60 °C and 76% at -90 °C. Triethylamine also
formed AAS but to a lesser extent. The amine R-hydro-
gens shifted from 2.47 to 3.10 ppm at -90 °C, where 24%
conversion to AAS was observed. The most important
result from these IR and NMR studies is the observation
of AAS under conditions used for ester formation. This
indicates the possibility of a nucleophilic catalysis mech-
anism.
To help interpret our AAS studies, we estimated the
relative AAS stabilities using SYBYL 6.0. The structure
of the AAS was drawn for a series of amines, and the
software determined the most stable conformation and
produced a minimized energy value for that conforma-
tion. Structures with lower minimized energy values
should form the AAS more readily. We obtained the
following ordering of calculated AAS stabilities, ranked
from most to least stable (SYBYL values given in
parentheses, kcal/mol): DMAP (15) > quinuclidine (25),
DABCO (25) > N-methylpiperidine (27) > Et2MeN (33)
> Et3N (36) > Pr3N (50). The calculated AAS stabilities
correlate with experimental data in Table 2.
Effect of Am in e Str u ctu r e on Ra te of P h en yl
Ben zoa te F or m a tion . Model reactions between benzoyl
chloride and phenol in the presence of various tertiary
amines were carried out to determine the effect of amine
basicity and structure on the reaction rate. The results
are given in Table 3. Table 3 is ordered with the most
effective catalysts at the top and the poorest catalysts at
the bottom. The rates listed are taken as the initial slope
of the concentration-time curves. The two rate deter-
mination methods (-d[BC]/dt versus d[PB]/dt) agree,
which is consistent with the absence of intermediates in
the IR spectrum during the experiment. The amines
chosen for this study represent a range of basicity and
nucleophilicity and include amines which gave high
yields of cyclic esters (quinuclidine and DABCO), moder-
ate yields (N-methylpiperidine), and low yields (triethyl-
amine). The reaction of DMAP with benzoyl chloride was
complete within the first IR scan, so only a lower limit
for the rate can be calculated. The reaction with quinu-

682 J . Org. Chem., Vol. 63, No. 3, 1998
Hubbard and Brittain
Ta ble 4. Bu tyl Ben zoa te F or m a tion : Ra te vs Am in ea
amineb
pKa
-d[BC]/dt,c M/s
d[BB]/dt,c M/s
DMAP
quinuclidine
N-MeP
9.45d
10.95e
10.19f
10.75e
>0.3
>1.5 × 10-6
1.5 × 10-5
3.7 × 10-6
≈0.1
≈0.1
6.3 × 10-5
Et3N
1.3 × 10-5
a
[BC]0 ) [butanol]0 ) [amine]0 ) 0.03 M, dichloromethane, 0
°C; all rate values are the average of at least two separate runs,
b
experimental error never exceeded 5% of reported value. N-MeP
) N-methylpiperidine. c -d[BC]/dt ) rate of benzoyl chloride loss,
d
d[BB]/dt ) rate of butyl benzoate formation. Reference 23.
e Reference 24. f Reference 26.
loss, -d[BC]/dt. The experiments in Table 4 were not
carried out at the same concentrations as phenol, so the
rates are not directly comparable. In general, butyl
benzoate formation was slower than phenyl benzoate
formation. In quinuclidine-catalyzed butyl benzoate
formation, the reaction was sufficiently fast that we can
only estimate the rate of reaction.
F igu r e 6. Reaction order experiment for quinuclidine-
catalyzed reaction of benzoyl chloride with butanol in dichlo-
romethane at 0 °C (concentrations given in the figure). The
left y-axis is the benzoyl chloride concentration for the equimo-
lar reaction and right y-axis is for the reaction with higher
benzoyl chloride and butanol concentrations.
The first conclusion from the data in Table 4 is the
disparity between -d[BC]/dt and d[BB]/dt for DMAP. The
loss of benzoyl chloride was the most rapid among the
amines studied; however, the formation of butyl benzoate
occurred at a rate that was 5 orders of magnitude slower
than benzoyl chloride loss! The large disparity between
acid chloride loss and ester formation can be explained
by a nucleophilic-catalysis mechanism in which the rate-
determining process is the second step (k-1 . k2, Scheme
2). Another possibility is that the AAS formation is a
competing process with a base-catalyzed process. If we
ignore quinuclidine since we could not precisely measure
its rates, there was also a difference in the rate of benzoyl
chloride loss and ester formation for the other amines.
For both N-methylpiperidine and triethylamine, ester
formation was slower. These results contrast those
obtained with phenyl benzoate formation where the rates
of benzoyl chloride loss and ester formation were com-
parable. However, we did not observe AAS formation in
the IR spectrum during the kinetic runs for these two
amines.
Given the unusual nature of the kinetics in the butyl
benzoate study, it is difficult to draw definitive conclu-
sions concerning correlations with amine basicity or
nucleophilicity (as deduced by calculated AAS stability).
Ra te Or d er . We attempted to study the rate order of
quinuclidine in butyl benzoate formation and obtained
surprising results. The reaction rate decreased as the
concentrations of butanol and benzoyl chloride were
increased. Figure 6 shows data for two experiments in
which the quinuclidine concentration was maintained at
0.0167 M. In one experiment, stoichiometric concentra-
tions (0.0165 M) of benzoyl chloride and butanol were
used; in the other run, a 5-fold higher concentration
(0.0825 M) of benzoyl chloride and butanol was used. If
the concentration of quinuclidine was kept constant and
the reaction orders a, b, and c were nonnegative in accord
with eq 6, then the reaction rate would be expected to
increase as the concentrations of benzoyl chloride and
butanol were increased.
F igu r e 7. Isotope effect for the reaction of benzoyl chloride
(BC) with butanol in the presence of quinuclidine in dichlo-
romethane at 0 °C; [BC]0 ) [butanol]0 ) [quinuclidine]0
0.0167 M.
)
concentration is high enough to assist the base-catalyzed
reaction of butanol. If the amine concentration is sub-
stantially lower than that of benzoyl chloride, then the
amine is consumed in the form of the AAS. Even though
the benzoyl chloride and butanol concentrations are
higher, the relatively lower amount of amine is insuf-
ficient to promote base-catalyzed reaction.
Isotop e Effect. The isotope effects during butyl
benzoate formation are shown in Figure 7 for the qui-
nuclidine-catalyzed reaction of benzoyl chloride with
butanol. The reactions using butanol (BuOH) displayed
a typical exponential decrease in benzoyl chloride con-
centration with time, but the results with butanol-O-d
(BuOD) were quite unusual. Only the first 20 s of the
reaction are shown in Figure 7, but the BuOD was
essentially unreactive over a period of about 2-3 h. A
primary isotope effect for a simple linear abstraction
should show a difference in rate between BuOH and
BuOD of a factor of 2-7, but the observed effect was
much larger; we estimate kH/kD > 100. This large isotope
effect was reproducible and provides evidence supporting
a general-base-catalyzed mechanism.
d[BC]
dt
-
) kobs[BC]a[quinuclidine]b[butanol]c (6)
Discu ssion
One possible explanation is a mechanism involving
both AAS formation and a base-catalyzed mechanism.
Facile ester formation will only occur once the amine
We interpreted the experimental evidence for the
amine-catalyzed formation of phenyl benzoate from ben-

Amine-Catalyzed Ester Formation
J . Org. Chem., Vol. 63, No. 3, 1998 683
ms at 16 cm-1 resolution or 200 ms at 4 cm-1 resolution.
Reagent solutions were prepared in the drybox. The stopped-
flow syringes were assembled and filled in the drybox. Under
positive argon flow, the syringe setup connected to the flow-
through IR cell equipped with a temperature-controlled jacket.
The IR cell contained CaF2 optical windows separated by 0.025
cm PTFE spacers. The output of the IR cell was connected to
a syringe. The stopped-flow syringes were immersed in an
ice bath, and the IR cell was cooled by a refrigerated circulating
bath set at 0 °C with 2-propanol as the cooling fluid. The
temperature of the experimental setup was allowed to equili-
brate for 30 min prior to beginning the experiment.
All rates were the average of at least two separate runs.
Run-to-run variation in the rates never exceeded 5%.
For two-component reactions, a two-syringe setup was used
with a component in each syringe. The three-component
reactions (benzoyl chloride, alcohol, and amine) were carried
out in one of two ways. In early experiments, reactions were
done using three syringes and two mixers. Each syringe
contained a separate component solution. The benzoyl chloride
solution syringe and the alcohol solution syringe were con-
nected to the mixer, and the output of that mixer was fed into
the second mixer, as was the output of the amine solution
syringe. In later reactions, a two-syringe setup was used with
a premixed solution of benzoyl chloride and alcohol in one
syringe. Results were the same for the two-syringe vs three-
syringe experiments. The advantage of the two-syringe setup
is the reduction in back pressure.
zoyl chloride and phenol in terms of a nucleophilic
mechanism. The analogous mechanistic study of butyl
benzoate produced interesting results. First and fore-
most, a large isotope effect is observed which is consistent
with a general-base-catalyzed process. But, at this time
we cannot fully reconcile the observed disparity in
-d[BC]/dt and d[BB]/dt nor the unusual rate-concentra-
tion dependence in the butyl benzoate rate studies. The
conclusion that the amine operates via a general-base-
catalysis mechanism in the butanol reaction makes it
difficult to accept the nucleophilic catalysis mechanism
for phenol. Relative to butanol, phenol would be more
likely to participate in a base-catalyzed process because
it is more acidic. Consequently, we cannot completely
resolve the mechanistic questions that motivated this
study.
What remains is heretofore unavailable rate informa-
tion for the amine-catalyzed reactions of benzoyl chloride
with alcohols. Furthermore, the sensitivity of the rate
of ester formation on small structural changes in the
tertiary amine is consistent with observed trends in the
yields of macrocyclic esters produced via similar chem-
istry. The amine structure exerts a powerful influence
over ester formation rates and, combined with control
over end-group concentration (by addition rates of reac-
tants to the reaction mixture), can be used to control the
yields of macrocyclic esters.
Molar absorptivities were determined by measuring the
absorbances of solutions of known concentration. Absorbances
were kept below 1 so Beer’s law would be obeyed.
P h en yl Ben zoa te Kin etics. The three-syringe technique
was used for tripropylamine, DABCO, DMAP, and triethyl-
amine. The two-syringe technique was used for diethyl-
methylamine, N-methylpiperidine, quinuclidine, and pyridine.
All experiments were run to produce an initial concentration
of 0.0167 M for each reactant.
To determine the reaction order of benzoyl chloride, phenol
and triethylamine concentrations were 0.167 M each and the
concentration of benzoyl chloride solution was varied from
0.005 to 0.033 M. For determination of the reaction order of
triethylamine, benzoyl chloride and phenol concentrations
were 0.1 M and triethylamine concentration varied from
0.0067 to 0.02 M. To determine the reaction order of phenol,
the concentrations of benzoyl chloride and triethylamine were
0.067 M and the phenol concentrations varied from 0.003 to
0.013 M.
For DABCO reaction order experiments, the concentrations
of benzoyl chloride and phenol were 0.025 M and the DABCO
concentration varied from 0.0025 to 0.005 M.
For isotope effect experiments in phenyl benzoate formation,
three-syringe experiments were used. When triethylamine
was the catalyst, the concentration of the reactants was 0.067
M each. This run was then compared with a similar one in
which the phenol was replaced with phenol-d6. When DABCO
was the catalyst, the concentration of reactions was 0.0167
M.
Bu tyl Ben zoa te Kin etics. Runs were carried out under
equimolar conditions using a two-syringe setup; the concentra-
tion of the reactants was 0.03 M. The isotope effect experi-
ments were run with 0.0167 M concentrations.
Mod elin g. Predictions of relative acylammonium salt
stability were carried out using SYBYL 6.0 on a Silicon
Graphics workstation. Structures were drawn in several
different conformations and each was energy-minimized to
verify that values obtained did not represent local energy
minima. Predictions of most favorable geometry were made
using a force-field method. The energy minimization routine,
MAXMIN2, used a conjugate gradient minimization method.
Exp er im en ta l Section
Rea gen ts. All reagents were purchased. Dichloromethane
was distilled from P2O5 under nitrogen. Benzoyl chloride was
refluxed with thionyl chloride overnight; the thionyl chloride
was removed in vacuo, and the benzoyl chloride was fraction-
ally distilled under vacuum. Triethylamine was fractionally
distilled twice from CaH2 under N2. DABCO was recrystal-
lized from diethyl ether. Quinuclidine was purified by subli-
mation. 4-(Dimethylamino)pyridine was purified by recrys-
tallization from toluene. Diethylmethylamine, tripropylamine,
pyridine, and N-methylpiperidine were refluxed over KOH for
16 h and then fractionally distilled under N2. Phenol, phenol-
d6, and butanol-O-d were used as received. Butanol was
fractionally distilled from Na. Dichloromethane-d2 was dried
over CaH2 and distilled using a bulb-to-bulb technique. Tet-
raethylammonium phenoxide was prepared by the reaction of
phenol with tetraethylammonium hydroxide; the product was
recrystallized in acetonitrile. All materials used for kinetics
experiments were stored and handled in an argon-filled
glovebox.
NMR Stu d ies. Variable-temperature NMR experiments
were carried out using a 400 MHz spectrometer. Amine
solutions (0.07 M) in 0.7 mL of dichloromethane-d2 were
prepared in the glovebox and transferred to NMR tubes with
screw-caps and rubber septa. The sample was cooled in the
NMR magnet (-60 to -90 °C) and the amine spectrum
recorded. Benzoyl chloride (0.07 mol, 8.13 µL) was added and
the spectrum recorded after reequilibration of temperature.
Stop p ed -F low Kin etics. Kinetic experiments were per-
formed using a stopped-flow FT-IR apparatus. Details of the
technique have been published before.27 An FTIR spectrom-
eter was used which is capable of taking a full spectrum in 50
(23) Aue, D. H.; Webb, H. M.; Davidson, W. R.; Toure, P.; Hopkins,
H. P., J r.; Moulik, S. P.; J ahagirdar, D. V. J . Am. Chem. Soc. 1991,
113, 1770.
(24) Arnett, E. M.; Mitchell, E. J .; Murty, T. S. S. R. J . Am. Chem.
Soc. 1974, 96, 3875.
(25) Hine, J .; Kaufmann, J . C.; Cholod, M. S. J . Am. Chem. Soc.
1972, 94, 4590.
(26) Dean, J . A. Handbook of Organic Chemistry; McGraw-Hill: New
York, 1987. Hine, J .; Chen, Y.-J . J . Org. Chem. 1987, 52, 2091.
(27) Brittain, W. J . J . Am. Chem. Soc. 1988, 110, 7440.
Ack n ow led gm en t. The authors would like acknowl-
edge helpful discussions with J oe King.
J O9716643